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1 Original Article Defining the at risk patients for contrast induced nephropathy after coronary angiography; 24-h urine creatinine versus Cockcroft-Gault equation or serum creatinine level Ahmadreza Assareh, Saeed Yazdankhah, Ahmad Ahmadzadeh 1, Mahdi Yadollahzadeh 2, Nasim Nasehi, Habib Haybar Department of Cardiology, Ahvaz Jundishapur University of Medical science, Golestan Hospital, Ahvaz, 1 Department of Hematology-Medical Oncology, Ahvaz Jundishapur University of Medical science, Golestan Hospital, Ahvaz, 2 Department of Internal Medicine, Shahid Beheshti University of Medical Sciences (SBMU), Tehran, Iran Background: Definitions of chronic kidney disease (CKD) in many catheterization laboratories have relied on the serum creatinine (Scr) rather than glomerular filtration rate (GFR). Regarding that CKD is the primary predisposing factor for contrast induced nephropathy (CIN), we compared the sensitivity of calculated GFR by 24-h Urine creatinine with Cockcroft-Gault (CG) equation and Scr level to define at risk patients for CIN who were undergone coronary angiography (CAG). Materials and Methods: Two hundred fifty four subjects who were candidate for CAG and had normal creatinine level were enrolled. Before CAG, GFR was calculated from a 24-h urine collection, CG equation and a single Scr sample regarding to previously described protocol. Contrast volume used for each case <100 ml. CIN was defined as a 0.5 mg/dl or 25% elevation in the Scr. Results: CIN occurred in 10.6%. Baseline GFR, the volume of contrast agent, and diabetes were the independent risk factors for CIN. GFR was less than 60 ml/min/1.73 m2 in 28% and 23.2% of patients regarding to 24-h urine creatinine and CG equation, respectively. In CIN prediction, 24-h urine creatinine estimated GFR had 85.2%, 59.3% and CG equation GFR had 78.9%, 81.1% sensitivity and specificity, respectively. Conclusion: Although, GFR estimated by CG equation has less sensitivity than GFR calculated from 24-h creatinine in CIN probability, but it is better than Scr alone and because of cost-effectiveness and convenience using of this method, we suggest at least using CG equation for GFR calculation before CIN, especially in diabetic and/or older than 60 years cases. Keywords: 24-hour urine creatinine, cockcroft-gault equation, contrast induced nephropathy, coronary angiography, glomerular filtration rate, serum creatinine INTRODUCTION Contrast induced nephropathy (CIN) is the third most prevalent preventable cause of acute kidney injury in hospitalized patients. [1] CIN increased mortality and morbidity specially in patients with cardiovascular diseases. [2] Diabetes mellitus (DM), chronic kidney disease (CKD), severe congestive heart failure (CHF), dehydration, hypotension, type and volume of contrast are risk factors for CIN. [3] Patients with renal failure are susceptible for Quick Response Code: Access this article online Website: DOI: *** atherosclerosis, which increased needs for coronary angiography (CAG). Also, many patients with cardiovascular disease have renal failure, or use drugs which could increase the risk of CIN such as angiotensin converting enzyme inhibitors (ACEIs). [4] The incidence of CIN after CAG reported as zero to 50%. [5] which was 40% in diabetic patients and 50 to 90% in CKD. [6] It seems many patients are at increased risk for CIN and in many of them CAG will be necessary. [7] So, preventive efforts from CIN should be performed for patients who candidate for CAG. Definition of CKD in many catheterization laboratories have relied on the serum creatinine (Scr) rather than creatinine clearance (Crcl) or glomerular filtration rate (GFR). Because there are many factors in addition to GFR which effect on Scr level, so using Scr alone is not enough to define at risk patients for CIN. The past researches suppose Cockcroft-Gualt (CG) equation or nutrition correction instead of Scr alone to determine the risk of CIN. [8,9] Address for correspondence: Dr. Habib Haybar, Cardiovascular Research Center, Ahvaz Jundishapur University of Medical science, Golestan Hospital, Ahvaz, Iran. dr.habibhaybar@yahoo.com Received: ; Revised: ; Accepted: Journal of Research in Medical Sciences September 2012

2 In this study, we compared the sensitivity of calculated GFR by 24-h Urine creatinine, CG equation and Scr level to define at risk patients for CIN who were undergone CAG. MATERIALS AND METHODS Two hundred fifty four (254) subjects who were candidate for CAG and fulfilled inclusion criteria were enrolled in this prospective study. Nephrotoxic drugs [(such as aminoglycosides, Nonsteroidal anti-inflammatory drugs (NSAIDs)] and drugs which established or unclear nephro-effective (as aminophylline, theophylline, prostaglandin E, ascorbic acid, N-acetyl cysteine and statins) was discontinued from two weeks before procedure. [3] Also, metformin replaced by insulin in DM cases. During the study if each of exclusion criteria presents in any time, the case was omitted from the study. Inclusion criteria 1. Did not have AKI or CKD presentation: AKI is defined by an abrupt (within 48 h) absolute increase in the serum creatinine concentration of 0.3 mg/ dl from baseline, or serum creatinine concentration increased ³50 percent, or oliguria of less than 0.5 ml/kg per hour for more than six hours. [10] CKD is defined based on the presence of either kidney damage or decreased kidney function for three or more months, irrespective of cause. As a routine estimated GFR is used to determined renal function (normal >90 ml/ min/1.73 m 2 ). Kidney damage, as defined by structural abnormalities or functional abnormalities other than decreased GFR. [11] 2. Did not received contrast during last week 3. Did not have any history of contrast sensitivity 4. Did not received diuretics/aceis/angiotensin receptor blockers during last 10 days 5. The permission of discontinuing nephrotoxic drugs (such as aminoglycosides, NSAIDs) or drugs which established or unclear nephro-effective (as aminophylline, theophylline, prostaglandin E, ascorbic acid, N-acetyl cysteine and statins). Exclusive criteria 1. Cardiopulmonary resuscitation (CPR) during CAG 2. Cardiogenic shock 3. Massive bleeding or hemodynamic instability during CAG 4. Acute pulmonary edema 5. Necessary to use renal effective drugs after CAG 6. Incorrect follow up after CAG and did not perform 48 h after CAG samples and tests 7. Contrast volume used more than 100 cc 8. Present of inclusion criteria number 3 or 5 during the study Before angiography Scr level and 24-h urine creatinine level was checked in all cases. If 24-h urine volume was less than 500 cc or more than 3000 cc or its creatinine level was less than (0.2 body weight) in males or (0.15 body weight) in females, the sample define as incorrect collected sample and the case was omitted from the study. Iodixanol (Visipaque, GE Medical, Inc) was used as contrast in all CAG candidates (the volume of contrast varied in each case by the minimum of need) Contrast volume used for each case <100 ml. After 48 h from angiography Scr level was checked in all cases. CIN was defined as a 25% elevation in the Scr or an absolute increase of 0.5 mg/dl, 48 h after CAG. GFR before CAG was calculated by 3 ways: 1. Based on Scr; 2. Based on CG equation; 3. Based on 24-h urine; [Scr: Serum Creatinine (mg/dl), age: years old (years), Ucr: 24-h urine creatinine (mg/dl), Uvol: 24-h Urine Volume (ml/min)] DM was defined as patients who had history of DM and used specific diabetic treatment, or who had fasting plasma glucose values 126 mg/dl (7.0 mmol/l) in two times measurement. [12] Heart failure (systolic) was defined as patients who had ejection fraction lower than 50% in coronary angiography. [13] Data were analyzed by SPSS 16 software with using independent T-test, Chi-square, Pearson correlation, logistic regression. GFR less than 60 ml/min was used to define high risk patients for CIN and sensitivity calculation. RESULT Two hundred eighty cases were enrolled in the study but 26 cases omitted because of incorrect follow-up. So, 254 cases remain in. Patient s demographic characteristics report in Table 1 completely. While the Scr was normal ( 60 ml/ min/1.73 m 2 ) in all subjects, GFR was less than 60 ml/ min/1.73 m 2 in 71 (28%) and 59 (23.2%) of patients regarding to 24-h urine creatinine and CG equation, respectively. There was significant correlations between GFRs estimated by Scr with GFR measured by 24-h creatinine clearance (Clcr) method (P < 0.001, r = 0.591) and GFR estimated Journal of Research in Medical Sciences September

3 by CG equation (P < 0.001, r = 0.726). The same, there was significant correlation between GFR estimated by CG equation and GFR measurement by 24-h Clcr method (P < 0.001, r = 0.799, Figure 1). Mean Scr (mean ± SD) before angiography was 1 ± 0.21 (mg/ dl) and after angiography was 1.05 ± 0.23 (mg/ dl) which has significantly difference (P value < 0.001). 27 cases (10.6%) catch CIN. In patients who complicated by CIN; 17 (63%) cases were male and 10 (37%) cases were female, 7 (25.9%) cases had HF and 20 (74.1%) cases did not have HF (differences were not significant), 9 (33.3%) cases were 60 years old and 18 (66.7%) cases were >60 years old, 19 (70.4%) cases were diabetic and 8 (29.6%) cases were non-diabetic (differences were significant by P values of and <0.001, respectively. The mean of consumed contrast volume was 88.7 ±31.2 ml in cases with CIN versus 71.6 ± 25.4 ml in cases without CIN (P = 0.001). GFR estimated by Scr was ± 13 ml/ min/1.73 m 2 in CIN group and was ± 26.7 ml/ min/1.73 m 2 in non-cin group (P = 0.449). GFR estimated by CG equation was 60.7 ± 22.1 ml/min/1.73 m 2 in CIN group versus 85.4 ± 33 ml/min/1.73 m 2 in non-cin group (P < 0.001). GFR measured by 24-h Clcr method was 48.2 ± 21 ml/min/1.73 m 2 in CIN group against of 78.8 ± 33.2 ml/ min/1.73 m 2 in non-cin group (P < 0.001). The regression analysis was performed to discover independent variables affected CIN so DM, contrast volume and GFR measured by 24-h Clcr method before CAG had significant regression [Table 2]. CIN occurs in 4 (2.2%) patients with GFR measured by 24-h Clcr method 60 ml/min/1.73 m 2 and in 23 (32.4%) patients with GFR measured by 24-h Clcr method <60, also in 11 (5.6%) cases with GFR estimated by CG equation 60 and in 16 (27.1%) cases with GFR estimated by CG equation <60 (P values were <0.001 in both, Table 3). Receiver Operating Characteristic (ROC) curves of GFR by 24-h urine Clcr with estimated GFR using CG equation and Scr level shows GFR estimated by Scr has distance from other two GFRs curves. These distances were prominent in cases more than 60 years old and in cases with diabetes mellitus [Figure 2]. Figure 1: Linear correlation between measured GFR by 24-h Urine Clcr with estimated GFR using CG equation and Scr level Table 1: Demographic characteristics of assessed patients Gender Male (%) 140 (55.1) Female (%) 114 (44.9) Age (year) Mean (SD) 56.6 (11.9) Weight (kg) Mean (SD) 72.3 (13.2) Disease DM (%) 57 (22.4) HF (%) 60 (23.6) DM+HF (%) 12 (4.7) GFR (ml/min) (Mean (SD) based on) Scr (25.6) 24-h Ucr 75.5 (33.4) CG equation 82.8 (32.8) DM = Diabetes Mellitus, HF = Heart failure, Scr = Serum creatinine, 24-h Ucr = 24-h Urine creatinine, CG equation = Cockcroft Gualt equation Table 2: Comparative analysis between contrast induced nephropathy subgroups by studied variables Variable Contrast induced nephropathy P value Positive(%) Negative(%) (regression * ) Gender Male 17 (63) 123 (54.2) Female 10 (37) 104 (45.8) Age (year) 60 9 (33.3) 155 (68.3) 0.001(r: ns*) > (66.7) 72 (31.7) DM Positive 19 (70.4) 38 (16.7) <0.001 Negative 8 (29.6) 189 (83.3) (r = 13.9*) HF Positive 7 (25.9) 53 (23.3) Negative 20 (74.1) 174 (76.7) Contrast volume (ml) 88.7 ± ± (r= 1.02*) GFR by Scr (ml/min) ± ± GFR by CG equation (ml/min) 60.7 ± ± 33 <0.001 (r: ns*) GFR by 24-h Ucr (ml/min) 48.2 ± ± 33.2 <0.001 (r = -0.92*) DM = Diabetes Mellitus, HF = Heart failure, Scr = Serum creatinine, 24-h Ucr = 24-h Urine creatinine, CG equation = Cockcroft Gualt equation, NS = Not significant; *Coefficients of regression analysis to defined independence factors affect CIN 861 Journal of Research in Medical Sciences September 2012

4 GFR measured by 24-h Clcr method had 85.2% sensitivity, 78.9% specificity, 32.4% and 87.8% positive and negative predictive values and 79.52% accuracy in predicting Table 3: Comparison of contrast induced nephropathy prevalence variable Contrast induced nephropathy Total P value Positive(%) Negative GFR by 24-h Ucr (ml/min) GFR by CG equation (ml/min) 60 4 (2.2) 179 (97.8) 183 (100) <0.001 <60 23 (32.4) 48 (67.6) 71 (100) (5.6) 184 (94.4) 195 (100) <0.001 <60 16 (27.1) 43 (72.9) 59 (100) 24-h Ucr = 24-h Urine creatinine, CG equation = Cockcroft Gualt equation GFR calculated based on serum creatinine in all cases was more than 60 ml/min/1.73 m 2 probability of contrast induced nephropathy. GFR estimated by CG equation had 59.3% sensitivity, 81.1% specificity, 27.1% and 94.4% positive and negative predictive values and 78.74% accuracy in predicting probability of contrast induced nephropathy. Complete information of diagnostic values is mentioned in Tables 4. DISCUSSION CIN has economic and clinical complications such as increased duration of hospitalization, dialysis need and mortality and morbidity risk. CIN prevalence were reported varies from 0 to 50% (up to 40% in diabetic patients and 50 to 90% in CKD) [6] by different mentioned factors. [5] In Cuvate (a) (a) (b) (c) (d) (e) Figure 2: Receiver Operating Characteristic (ROC) curves of GFR by 24-h Urine Clcr with estimated GFR using CG equation and Scr level. A: Overal, B: in cases 60 years old, C: in cases > 60 years old, D: in cases without diabetes mellitus, E: in cases with diabetes mellitus Journal of Research in Medical Sciences September

5 Table 4: Comparison of diagnostic values of GFRs calculated by 24-h urine creatinine and CG equation to predict probability contrast induced nephropathy Sensitivity (95%CI) Specificity (95%CI) Positive predictive value (95%CI) Negative predictive value (95%CI) Accuracy (95%CI) GFR by 24-h Ucr (ml/min) 85.2% ( ) 78.9% ( ) 32.4% ( ) 87.8% ( ) 79.52% ( ) GFR by CG equation (ml/min) 59.3% (39-77) 81.1% ( ) 27.1% ( ) 94.4% ( ) 78.74% ( ) 24-h Ucr = 24-h urine creatinine, CG equation = Cockcroft Gualt equation country, Ghani et al. fined 5.52% CIN from 247 cases, [14] Valente et al. report 10.8%, [15] and Kim report 13% [8] CIN s in their research. Also, in other CIN reported as 13% and 20% in non-diabetic and diabetic patients, respectively. [16] In-hospital CIN developed in 72 (8.3%) patients, in Mager et al. report [17] and 5.2% in Worasuwannarak and Pornratanarangsi s report. [18] The same as these researches in our study CIN prevalence was 10.6%. There was wide variation in risk factors, which contributes with CIN. There were age over 75 years old, DM, CHF, pulmonary edema history, contrast volume, serum creatinine over 1.5 mg/dl and GFR less than 60 ml/ min/1.73 m 2 as risk factors for CIN in Rihale and Baret studies. [19,20] Beckris confirmed them and added dehydration as a CIN s risk factor. [21] Kim et al. report left ventricular ejection fraction less than 40%, GFR less than 60 ml/min/1.73 m 2, serum reactive protein C more than 0.5 mg/dl and contrast volume consumption more than 250 cc as CIN s independent risk factors. [8] Basal Scr level, shock, female gender, DM were CIN s risk factors in report of Ghani et al. [11] Renal underlying disease, hemodynamic instability, dyslipidemia, hypotension after angiography were risk factors for CIN in Valente et al. research. [22] In the same pattern in our study, independent risk factors for CIN were basal GFR, DM, and contrast volume [Table 3]. National kidney foundation define a single system for chronic renal disorders classification, based on GFR during 2002 and suggest to use CG equation or modification of diet in renal disease (MDRD) for GFR estimation. [23] This real despite of limitations in these equations (as over estimation of GFR in CG equation and did not use body surface area, the same as GFR estimation in MDRD equation), but also it is better for determining CKD staging rather than Scr level alone. Similarly in our study, ROC curves in Figure 2 shows GFRs based on CG equation and 24-h Clcr method have similar pattern than to GFR based on Scr, especially in subgroups of age and DM. So, sensitivity and specificity of both GFRs based on CG equation and 24-h urine Clcr seems more similar than to GFR estimated by Scr, especially in patients over 60 years old or DM. According to Table 4, it was cleared that, CG equation is better than Scr alone for GFR estimation. Although, this equation has less sensitivity than GFR, calculated from 24-h creatinine in CIN probability, but 24-h urine collection needs more time and it is more expensive than estimating GFR using equations, so CG equation seems more convenience as it is cost effective as a simple method for physicians in their practice, especially in cases over 60 years old or DM. On the other hand, using GFR based on CG equation could reveled at least 28% of cases with GFR < 60 ml/min/1.73 m 2 and high risk for CIN more than using Scr alone or GFR based on Scr. CONCLUSION GFR by 24-h urine Clcr is more accurate way to estimate GFR in patients who candidate for CAG, but it needs more time, cost and hospitalization. While using CG equation for GFR calculation to assess CIN s risk in patients is more applicable than Scr level alone. Although, estimating the GFR using this equation has less sensitivity than GFR calculated from 24-h creatinine in CIN probability, but because of cost-effectiveness, we suggest using CG equation for GFR calculation before CIN, to choose patients who need more attention for preventive support, especially in cases over 60 years old or DM. ACKNOWLEDGMENT Special thanks to Golestan Hospital Clinical development research center (Molook Salemzadeh and Asadallah Cheraghi for data collection) for methodology and submission consultation. REFERENCES 1. Gupta R, Birnbaum Y, Uretsky BF. The renal patient with coronary artery disease: Current concepts and dilemmas. J Am Coll Cardiol 2004;44: Murphy SW, Barrett BJ, Parfrey PS. Contrast nephropathy. J Am Soc Nephrol 2000;11: Schweiger MJ, Chambers CE, Davidson CJ, Blankenship J, Bhalla NP, Block PC, et al. Prevention of contrast induced nephropathy: Recommendations for the high risk patient undergoing cardiovascular procedures. Catheter Cardiovasc Interv 2007;69: Porter GA. Contrast-associated nephropathy. Am J Cardiol 1989;64:22E-6E. 5. Boccalandro F, Amhad M, Smalling RW, Sdringola S. Oral acetylcysteine does not protect renal function from moderate to high doses of intravenous radiographic contrast. Catheter Cardiovasc Interv 2003;58: Gleeson TG, Bulugahapitiya S. Contrast-induced nephropathy. 863 Journal of Research in Medical Sciences September 2012

6 AJR Am J Roentgenol 2004;183: Shyu KG, Cheng JJ, Kuan P. cetylcysteine protects against acute renal damage in patients with abnormal renal function undergoing a coronary procedure. J Am Coll Cardiol 2002;40: Kim U, Kim YJ, Lee WJ, Lee SH, Hong GR, Park JS, et al. The estimated glomerular filtration rate with using the mayo clinic quadratic equation as a new predictor for developing contrast induced nephropathy in patients with angina pectoris. Korean Circ J 2008;38: Verhave JC, Fesler P, Ribstein J, du Cailar G, Mimran A. Estimation of renal function in subjects with normal serum creatinine levels: Influence of age and body mass index. Am J Kidney Dis 2005;46: Chertow GM, Burdick E, Honour M, Bonventre JV, Bates DW. Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J Am Soc Nephrol 2005;16: Levey AS, Coresh J. Chronic kidney disease. Lancet 2012;379: American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2010;33 Suppl 1:S62-9. Erratum in: Diabetes Care 2010;33:e Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, et al focused update incorporated into the ACC/ AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: Developed in collaboration with the International Society for Heart and Lung Transplantation. Circulation 2009;119:e Erratum in Circulation. 2010;121:e Ghani AA, Tohamy KY. Risk score for contrast induced nephropathy following percutaneous coronary intervention. Saudi J Kidney Dis Transpl 2009;20: MacNeill BD, Harding SA, Bazari H, Patton KK, Colon-Hernadez P, DeJoseph D, et al. Prophylaxis of contrast-induced nephropathy in patients undergoing coronary angiography. Catheter Cardiovasc Interv 2003;60: McCullough PA. Interface between Renal Disease and Cardiovascular Illness. In: Libby P, Bonow RO, Mann DL, Zipes DP, editors. Libby: Braunwald s Heart Disease: A Textbook of Cardiovascular Medicine, 8 th ed. Philadelphia, Saunders; 2007: Mager A, Vaknin Assa H, Lev EI, Bental T, Assali A, Kornowski R. The ratio of contrast volume to glomerular filtration rate predicts outcomes after percutaneous coronary intervention for ST-segment elevation acute myocardial infarction. Catheter Cardiovasc Interv 2011;78: Worasuwannarak S, Pornratanarangsi S. Prediction of contrastinduced nephropathy in diabetic patients undergoing elective cardiac catheterization or PCI: Role of volume-to-creatinine clearance ratio and iodine dose-to-creatinine clearance ratio. J Med Assoc Thai 2010;93 Suppl 1:S Rihal CS, Textor SC, Grill DE, Berger PB, Ting HH, Best PJ, et al. Incidence and prognostic importance of acute kidney injury after percutaneous coronary intervention. Circulation 2002;105: Barrett BJ, Parfrey PS, Vavasour HM, McDonald J, Kent G, Hefferton D, et al. Contrast nephropathy in patients with impaired renal function: High versus low osmolar media. Kidney Int 1992;41: Barrett BJ, Carlisle EJ. Metaanalysis of the relative nephrotoxicity of high- and low-osmolality iodinated contrast media. Radiology 1993;188: Valente S, Lazzeri C, Giglioli C, Margheri M, Comeglio M, Nicolaci L, et al. Contrast-induced nephropathy in urgent coronary interventions. J Cardiovasc Med (Hagerstown) 2006;7: Levey AS, Coresh J, Balk E, Kausz AT, Levin A, Steffes MW, et al. National Kidney Foundation practice guidelines for chronic kidney disease: Evaluation, classification, and stratification. Ann Intern Med 2003;139: How to cite this article: Assareh A, Yazdankhah S, Ahmadzadeh A, Yadollahzadeh M, Nasehi N, Haybar H. Defining the at risk patients for contrast induced nephropathy after coronary angiography; 24-h urine creatinine versus Cockcroft-Gault equation or serum creatinine level. J Res Med Sci 2012;17: Source of Support: Nil, Conflict of Interest: None declared. Journal of Research in Medical Sciences September

Contrast Induced Nephropathy

Contrast Induced Nephropathy O CIAKI refers to an abrupt deterioration in renal function associated with the administration of iodinated contrast media O CIAKI is characterized by an acute (within 48 hours)